Abstract 1146: Bone Marrow Cells that Abundantly Express Angiotensin AT1 and AT2 Receptors Modulate Vascular Repair by Regulating Mobilization and Differentiation of Smooth Muscle Cell Progenitors and Macrophage Activation
[BACKGROUND] Bone marrow (BM) cells and angiotensin II (Ang II) are involved in atherosclerosis and vascular repair after arterial injury, whereas AngII-mediated action on BM cells remains undefined.
[METHOD AND RESULT] Ligand binding assay showed that BM-derived mononuclear cells (BM-MNCs) expressed the abundant densities of AT1 and AT2 receptors. Total BM cells from AT1-deficient (AT1-KO), AT2-deficient (AT2-KO), or WT mice were transplanted into BM-ablated WT mice. A spring-wire was inserted into the femoral artery and analyzed 2 weeks after injury. Intima/media ratio was markedly increased in BMTAT2-KO→WT compared with BMTWT→WT (0.65 ± 0.1 vs 0.32 ± 0.1, p<0.05), whereas the ratio was much lower in BMTAT1-KO→WT mice (0.17 ± 0.04, p<0.05). Total area of reendothelialization 1 week after injury did not differ between three groups. Circulating potential smooth muscle cell (SMC) progenitors defined by c-kit-/lin-/sca-1+ markers were analyzed by flow cytometry. BMTAT2-KO→WT had markedly higher numbers of SMC progenitors after injury than BMTWT→WT mice (144 ± 42 and 21 ± 6 cells/μl, p=0.03), without any difference between BMTAT1-→KO→WT and BMTWT→WT. Basal number of circulating monocyte (Gr-1−/CD11b+) before injury did not differ between three groups, while BMTAT1-KO→WT had much smaller number (55% decrease, p=0.03) than BMTWT→WT after arterial injury, concomitant with reduced monocyte/macrophage recruitment in the neointima and adventitia. Although the numbers of circulating monocyte and migrating inflammatory cells did not differ between BMTAT2-KO→WT and BMTWT→WT, the activity of peritoneal macrophages, assessed by LPS-stimulated release of interleukin-1β and TNF-α, was notably augmented in AT2-KO (124 % and 160 %, respectively, p<0.05) compared with WT.
[CONCLUSION] BM-MNCs expressed the abundant densities of AT2 than AT1, and AT2-mediated signals on BM-MNCs inhibited neointimal formation after arterial injury, in contrast AT1 deteriorated the lesions. BM-AT1 and BM-AT2 differentially regulates the differentiation and/or proliferation of BM-derived SMC progenitors and the activation of inflammatory cells, suggesting that BM-AT2 could be an alternative target for the prevention of cardiovascular event.